Protease-activated receptor-1 mediates protection elicited by thrombin preconditioning in a rat 6-hydroxydopamine model of Parkinson's disease
Protease-activated receptor-1 mediates protection elicited by thrombin preconditioning in a rat 6-hydroxydopamine model of Parkinson's disease
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DOI：
10.1016/j.brainres.2006.07.094
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发表时间：
2006-10-20
期刊：
影响因子：
2.9
通讯作者：
Xi, Guohua
中科院分区：
文献类型：
--
作者：
Cannon, Jason R.;Keep, Richard F.;Xi, Guohua
帕金森病的病因仍然知之甚少，目前的治疗方案不能减缓疾病进展。最近，化学（凝血酶）预处理（TPC）被发现在6-羟基多巴胺（6-OHDA）疾病模型中具有保护作用。理解这些凝血酶诱导的保护作用背后的机制是重要的。本研究在大鼠中进行，以确定TPC的保护作用是否通过激活蛋白酶激活受体（PAR）介导。在单侧6-OHDA给药（10 μ g进入内侧前脑束）前3天，测试了用PAR-1和PAR-4的激动剂肽的特异性局部输注的预处理。此外，还检查了PAR-1拮抗剂与TPC的联合给药。在神经行为评估电池，PAR-1激动剂预处理提供了保护触须引起的前肢放置测试，前肢使用不对称测试，和一个角落转测试。此外，加入PAR-1拮抗剂可阻止TPC引起的保护作用。与PAR-1激动剂的作用相反，PAR-4激动剂预处理没有提供这种保护。事实上，在低剂量6-OHDA（5 μ g）模型中，PAR-4预处理显著增加了行为缺陷。这些结果表明TPC在该模型中的保护作用是通过PAR-1活化介导的。PAR-1和TPC对6-OHDA诱导的行为缺陷的影响似乎都不是通过多巴胺（DA）含量保留来介导的。PAR-1和PAR-4在帕金森病实验模型中的有害作用的进一步机制研究是必要的。(c)2006 Elsevier B. V.保留所有权利。
The etiology of Parkinson's disease remains poorly understood, and current treatment options do not slow disease progression. Recently, chemical (thrombin) preconditioning (TPC) was found to be protective in a 6-hydroxydopamine (6-OHDA) model of the disease. it is important to understand the mechanisms behind these thrombin-induced protective effects. The current study was conducted in the rat to determine whether the protective effects of TPC are mediated via activation of protease-activated receptors (PARs). Preconditioning with specific local infusion of agonist peptides for PAR-1 and PAR-4 3 days before unilateral 6-OHDA administration (10 mu g into the medial forebrain bundle) was tested. In addition, co-administration of a PAR-1 antagonist with TPC was examined. In a neurobehavioral assessment battery, PAR-1 agonist preconditioning provided protection in a vibrissae-elicited forelimb placing test, a forelimb-use asymmetry test, and a corner turn test. In addition, inclusion of a PAR-1 antagonist prevented the protective effects elicited by TPC. In contrast to the effects of the PAR-1 agonist, PAR-4 agonist preconditioning afforded no such protection. indeed, in a lower-dose model of 6-OHDA (5 mu g), PAR-4 preconditioning significantly increased behavioral deficits. These results indicate that the protective effects of TPC in this model are mediated through PAR-1 activation. Neither the effects of PAR-1 nor TPC on later 6-OHDA-induced behavioral deficits appeared to be mediated through dopamine (DA) content sparing. Further mechanistic studies on the actions of PAR-1 and PAR-4 as detrimental in experimental models of Parkinson's disease are warranted. (c) 2006 Elsevier B.V. All rights reserved.